Introduction: Several subsets of uterine natural killer lymphocytes (uNK cells) home to early decidua basalis in rodents and humans. UNK cells peak at midgestion when uNK cells synthesizing the angiokines placenta growth factor (PGF), vascular endothelial growth factor (VEGF) and Delta-like ligand 1 (DLL1) are dominant. UNK cell-driven angiogenesis regulates the timing of both uterine lumen closure and early, post-implantation conceptus development. UNK cells contribute to orthogonal branching and pruning of nascent decidual vessels and initiate spiral arterial remodeling. Physiological impact of the absences of uNK cells or of PGF were addressed and localized to maternal and fetal/offspring cardiovascular systems.
Materials and methods: Pregnancies were compared between mice without lymphocytes, with partial or full lymphocyte sufficiency or with genetic deletion of Pgf. All studies were conducted under approved animal utilisation protocols and in compliance with Canadian guidelines. Techniques used included histology, ultrasound or chronic continuous radiotelemetry recordings over pregnancy, analyses of cerebral and renal circulations and cognitive behavioural testing.
Results and discussion: The normal pattern of gestational blood pressure regulation (stable to gestation day (gd)5, decline to nadir at gd9, rebound towards baseline at gd10 and stable to term) was present in alymphoid mice lacking spiral arterial modification. In Pgf−/− mice, blood pressure decline was twice as large and nadir was 5 days, implicating PGF in normal gestational blood pressure stabilization. Ultrasonographic cardiac parameters in pregnant alymphoid or Pgf−/− mice differed from controls by gd14 and suggested left ventricular damage. In alymphoid but not Pgf−/− pregnancies, fetal cardiac function was additionally altered. Pgf−/− fetuses and offspring had poorly interconnected cerebral vessels that impacted on stroke susceptibility and cognitive functions. These studies highlight the importance of very early uNK cell functions and of PGF in normal postpartum health.
Funding: NSERC, CIHR, CFI and the Canada Research Chairs Programs.
02 - 04 Sep 2014
World Congress of Reproductive Biology